{"gene":"SLC7A7","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":1999,"finding":"SLC7A7 (encoding y+LAT-1) was identified as the gene mutated in lysinuric protein intolerance (LPI); a missense mutation in y+LAT-1 abolishes dibasic amino acid (cationic amino acid) transport activity when co-expressed with the heavy chain of 4F2hc (CD98) in Xenopus laevis oocytes, establishing that y+LAT-1 requires 4F2hc as a co-subunit for transport function.","method":"Mutation identification in patients + functional expression assay in Xenopus oocytes + transport activity measurement","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct transport reconstitution in oocytes with mutagenesis, replicated across two independent papers in the same issue","pmids":["10080182","10080183"],"is_preprint":false},{"year":2000,"finding":"Five LPI-causing mutations (L334R, G54V, 1291delCTTT, 1548delC, and LPIFin) were functionally characterized: all abolished y+L amino acid transport when co-expressed with 4F2hc in Xenopus oocytes. Frameshift mutants (1291delCTTT, 1548delC, LPIFin) were retained intracellularly, while missense mutants L334R and G54V reached the plasma membrane, demonstrating that residues L334 and G54 are critical for transport catalytic function rather than membrane targeting.","method":"Expression in Xenopus oocytes, transport activity assays, immunostaining/subcellular localization","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in oocytes with multiple mutants, mutagenesis coupled to localization, orthogonal methods in one study","pmids":["10655553"],"is_preprint":false},{"year":2000,"finding":"SLC7A7 (y+LAT-1) gene comprises 10 exons; novel LPI mutations include missense M1L (start codon change), missense S386R, nonsense W242X, splice mutations IVS3+1G>A and IVS6+1G>T, insertion 786insT, and deletions 455delCTCT and 1425delTTCT, all causing loss of functional cationic amino acid transport.","method":"Genomic sequencing, mutational analysis","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mutational characterization of gene structure with multiple mutations identified; no functional reconstitution per abstract","pmids":["10631139"],"is_preprint":false},{"year":2000,"finding":"In LPI fibroblasts, arginine transport through system y+L is normal (not defective), attributable to SLC7A6 (y+LAT2) activity rather than SLC7A7 (y+LAT1), demonstrating cell-type-specific compensation between paralogs. Both SLC7A7 and SLC7A6 are expressed in fibroblasts, and the LPI transport defect is limited to epithelial cells where SLC7A7 predominates.","method":"Amino acid transport characterization (bidirectional flux assays, inhibitor profiling with NEM, membrane potential, Na+ dependence) in patient-derived and control fibroblasts; mRNA expression analysis","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transport characterization in primary patient cells with multiple pharmacological inhibitors; single lab","pmids":["11078698"],"is_preprint":false},{"year":2005,"finding":"The LPI-causing y+LAT-1 mutant E36del displays a partial dominant-negative effect on y+LAT-2 activity when co-expressed in Xenopus oocytes and mammalian cells, suggesting a multiheteromeric structure for both [4F2hc/y+LAT-1] and [4F2hc/y+LAT-2] complexes and interference between y+LAT-1 and y+LAT-2 proteins that can explain why upregulation of SLC7A6 does not fully compensate for SLC7A7 loss in LPI.","method":"Expression in Xenopus laevis oocytes and mammalian cells, transport activity assays, dominant-negative functional analysis","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct transport reconstitution with mutants in oocytes and mammalian cells; single lab, partial mechanistic follow-up","pmids":["15756301"],"is_preprint":false},{"year":2005,"finding":"Functional analysis of eight SLC7A7 mutations by expression in Xenopus oocytes or patient renal tubular cells revealed loss of y+L transport activity. The R333M mutation disrupts a functional splicing motif (last nucleotide of exon 7), generating misspliced transcripts in addition to protein dysfunction.","method":"Expression in Xenopus oocytes, transport activity assay, analysis of patient renal tubular cells, splicing analysis","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — transport reconstitution in oocytes and patient cells; single lab","pmids":["15776427"],"is_preprint":false},{"year":2006,"finding":"y+LAT-1 (SLC7A7) is the transporter responsible for uptake of the iNOS inhibitor GW274150 in murine macrophage J774 cells, operating via system y+L (Na+-independent, trans-stimulated, inhibited by cationic amino acids and neutral amino acids in a Na+-dependent manner). Northern blot confirmed expression of y+LAT-1 but not y+LAT-2 transcripts in these cells.","method":"Saturable transport assay with pharmacological profiling (inhibitors, ion substitution, trans-stimulation), Northern blot","journal":"Amino acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — detailed kinetic and pharmacological transport characterization; single lab, two orthogonal methods","pmids":["16699825"],"is_preprint":false},{"year":2006,"finding":"Two alternative promoters regulate SLC7A7 expression: a novel TATA-box-containing downstream promoter upstream of exon 2 is active in tissues with strong cationic amino acid transport defects in LPI patients, revealing tissue-specific transcriptional regulation of the gene.","method":"Promoter identification and analysis, tissue-specific expression studies","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct identification of alternative promoter with functional evidence; single lab, single study","pmids":["17196863"],"is_preprint":false},{"year":2007,"finding":"y+LAT-1 and 4F2hc form a heterodimer that assembles prior to reaching the plasma membrane; FRET (acceptor photobleaching) microscopy in HEK293 cells showed the interaction occurring in the endoplasmic reticulum and Golgi complex as well as at the plasma membrane, providing direct evidence that 4F2hc acts as a chaperone to assist trafficking of y+LAT-1 to the plasma membrane.","method":"Acceptor photobleaching FRET microscopy in HEK293 cells expressing fluorescently-tagged y+LAT-1 (ECFP) and 4F2hc (EYFP)","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct FRET measurement in intact cells demonstrating protein-protein interaction at specific subcellular compartments with functional chaperone inference; single lab with rigorous optical method","pmids":["17560897"],"is_preprint":false},{"year":2007,"finding":"Slc7a7 knockout mice (gene-trap retroviral insertion) exhibit intrauterine growth restriction (IUGR) and neonatal lethality. IUGR is mechanistically linked to marked downregulation of insulin-like growth factor 1 (IGF-1) in fetal liver, demonstrated by quantitative real-time RT-PCR, immunostaining, and Western blot. Adult surviving Slc7a7-/- mice show metabolic derangement consistent with human LPI after protein ingestion.","method":"Mouse knockout (retroviral gene-trap), quantitative RT-PCR, immunostaining, Western blot, DNA microarray gene expression profiling","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mouse model with defined molecular phenotype (IGF-1 downregulation), three orthogonal quantification methods; published in peer-reviewed journal","pmids":["17376816"],"is_preprint":false},{"year":2013,"finding":"FACS-FRET analysis confirmed that heteromerization of y+LAT1 with 4F2hc is not disrupted by any tested LPI mutations (including missense and frameshift mutants), but LPI mutant y+LAT1 proteins are expressed at significantly lower levels and cause markedly increased cellular mortality compared to wild-type y+LAT1.","method":"FACS-FRET (flow cytometry-based FRET) in cells expressing CFP-tagged y+LAT1 and YFP-tagged 4F2hc","journal":"General physiology and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET-based protein interaction assay with multiple LPI mutants; single lab","pmids":["23940088"],"is_preprint":false},{"year":2016,"finding":"CDX2, an intestine-specific transcription factor, directly binds the SLC7A7 promoter (demonstrated by luciferase reporter and chromatin immunoprecipitation assays) and activates SLC7A7 transcription, establishing SLC7A7 as a direct CDX2 target gene in intestinal epithelial cells.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), overexpression in IPEC-1 cells","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (reporter assay and ChIP) in a single study; single lab","pmids":["27121315"],"is_preprint":false},{"year":2018,"finding":"Silencing of SLC7A7/y+LAT1 in human THP-1 macrophages and A549 airway epithelial cells via siRNA induces expression and release of IL-1β and TNFα independent of intracellular arginine levels, via activation of the NFκB signaling pathway at the transcriptional level. Furthermore, SLC7A7 silencing potentiates IL-1β-stimulated CCL5/RANTES expression without affecting CXCL8/IL-8, revealing a non-transport immunomodulatory function of y+LAT1.","method":"siRNA knockdown, ELISA, qRT-PCR, NFκB pathway analysis in THP-1 macrophages and A549 cells","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular pathway (NFκB) using multiple cell types and multiple readouts; single lab","pmids":["29616026"],"is_preprint":false},{"year":2019,"finding":"y+LAT1 (SLC7A7) is the dominant arginine transporter in monocyte-derived macrophages and intestinal Caco-2 cells, while y+LAT2 (SLC7A6) dominates in fibroblasts. At the basolateral side of Caco-2 cells, system y+L mediates arginine efflux in exchange with leucine plus sodium, explaining defective intestinal absorption/reabsorption of arginine in LPI.","method":"Kinetic transport assays, mRNA expression analysis across multiple human cell types (MDM, Caco-2, HRPTEpC, fibroblasts), siRNA knockdown","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative transport kinetics across multiple cell types with molecular identification; single lab, multiple orthogonal approaches","pmids":["31705628"],"is_preprint":false},{"year":2019,"finding":"Three LPI-causing y+LAT1 mutations reproduced as eGFP-tagged proteins in CHO cells result in defective arginine transport and retention of the mutant proteins in the cytosol (confirmed by confocal microscopy), with heterogeneous subcellular distribution patterns among mutants. System y+L activity is impaired in monocytes from LPI patients but not in lymphoblasts carrying the same mutations, attributed to differential SLC7A7 mRNA expression between cell types.","method":"eGFP-tagged mutant expression in CHO cells, confocal microscopy, transport assays in transfected CHO cells and ex vivo patient monocytes/lymphoblasts","journal":"Orphanet journal of rare diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transport assay plus direct localization microscopy in two model systems; single lab","pmids":["30832686"],"is_preprint":false},{"year":2019,"finding":"A tamoxifen-inducible Slc7a7 knockout mouse recapitulates human LPI phenotype including malabsorption and impaired reabsorption of cationic amino acids, hypoargininemia, hyperammonemia, pulmonary alveolar proteinosis, and neurological impairment. Citrulline treatment improves metabolic derangement and survival, confirming the mechanistic link between y+LAT1 deficiency, cationic amino acid depletion, and hyperammonemia.","method":"Tamoxifen-inducible conditional knockout mouse, metabolic analysis (plasma/urine amino acids), histopathology, citrulline rescue experiment","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible KO mouse with defined metabolic phenotype, multiple organ systems analyzed, pharmacological rescue; peer-reviewed","pmids":["31653080"],"is_preprint":false},{"year":2020,"finding":"In zebrafish, Slc7a7 is the main cationic amino acid transporter expressed in macrophages; its expression is induced within 1–2 hours upon efferocytosis (phagocytosis of apoptotic cells). Slc7a7-deficient macrophages that engage in sustained efferocytic work die, demonstrating that Slc7a7 is required for macrophage survival during intense phagocytic activity, likely to cope with catabolism of dead cell material.","method":"Zebrafish genetic mutant screen, live imaging, macrophage lineage tracing, in vivo efferocytosis assay, gene expression analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function in zebrafish with defined cellular phenotype (macrophage death upon efferocytosis), induction kinetics measured, orthogonal in vivo and molecular methods","pmids":["32973110"],"is_preprint":false},{"year":2020,"finding":"Global Slc7a7 knockout mice (CRISPR/Cas9, exons 3–4 deletion) on mixed background display reduced plasma and increased urinary cationic amino acids, proximal tubular dysfunction (loss of brush border, lipid vacuolation in renal cortex), delayed skeletal development with decreased mineralization, and perinatal lethality on inbred backgrounds, recapitulating human LPI.","method":"CRISPR/Cas9 knockout mouse generation, amino acid quantification in plasma/urine, histopathology, micro-computed tomography","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent CRISPR KO mouse lines with defined molecular and organ phenotypes; peer-reviewed","pmids":["32504080"],"is_preprint":false},{"year":2022,"finding":"ATF3 transcriptionally activates SLC7A7 by binding to its enhancer region, and through this axis suppresses mTORC1 signaling to inhibit lipogenesis in hepatocellular carcinoma (HCC). Functional assays in ATF3-overexpressing and knockdown HCC cell lines confirmed that SLC7A7 acts downstream of ATF3 to restrain mTORC1 activity.","method":"Transcriptomic analysis, ATF3 overexpression/knockdown in HCC cell lines, chromatin/enhancer binding assay, mTORC1 activity assay, lipogenesis assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function experiments with defined signaling pathway placement; single lab","pmids":["39996726"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of the human y+LAT1–4F2hc complex were determined in two conformations: apo inward-open and substrate-bound outward-open states. Structural analysis identified Asp243 in y+LAT1 as critical for sodium ion coordination and substrate selectivity. Molecular dynamics simulations revealed different transport mechanisms for cationic versus neutral amino acids, and the structural framework explained the molecular basis of LPI-causing mutations.","method":"Cryo-EM structure determination (two conformations), molecular dynamics simulation, functional transport assay in mammalian cells","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures at two conformational states with functional transport validation and MD simulations; single study with multiple orthogonal methods","pmids":["40106545"],"is_preprint":false},{"year":2025,"finding":"Macrophage-specific deletion of Slc7a7 in atherosclerotic mice accelerates disease with more complex necrotic core composition. Slc7a7-silenced macrophages have reduced glutamine influx and reduced GLS1-dependent glutaminolysis, impairing downstream signaling for restorative macrophage functions. This establishes SLC7A7-dependent glutamine uptake as upstream of glutaminolysis and macrophage metabolic reprogramming in atherosclerosis.","method":"Macrophage-specific conditional Slc7a7 knockout in atherosclerosis mouse model, in vitro Slc7a7 silencing, glutamine flux measurement, glutaminolysis assay, histopathology","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO in disease model with defined metabolic mechanism (glutamine influx/glutaminolysis), in vitro and in vivo validation, peer-reviewed","pmids":["40983679"],"is_preprint":false},{"year":2025,"finding":"Defective erythropoiesis in Slc7a7 whole-body knockout mice is not caused by intrinsic loss of Slc7a7 in erythroblasts or myeloid cells (erythroblast- and myeloid-specific KOs do not recapitulate the phenotype; bone marrow transplants do not rescue), but is linked to impaired erythropoietin production in the kidney and subsequent iron overload.","method":"Whole-body and cell-type-specific conditional Slc7a7 knockouts (erythroblast- and myeloid-specific), bone marrow transplantation experiments, erythropoiesis analysis, erythropoietin measurement","journal":"Molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional KO models plus bone marrow transplant epistasis experiments definitively localizing the cell-non-autonomous defect; peer-reviewed","pmids":["39881295"],"is_preprint":false},{"year":2022,"finding":"Glucocorticoid (dexamethasone) reduces SLC7A7 expression in porcine skeletal muscle cells via changes in m6A mRNA modification, and reduced SLC7A7 expression in turn reduces mTOR signaling pathway activity and protein synthesis.","method":"Dexamethasone treatment of porcine skeletal muscle cells, m6A modification analysis, mTOR pathway readouts, protein synthesis assay","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect pathway placement via m6A and mTOR readouts in porcine cells with limited mechanistic detail in abstract","pmids":["35054897"],"is_preprint":false},{"year":2003,"finding":"The SLC7A7 promoter region (upstream of exon 1) lacks classical TATA-box and Inr elements but contains E-box and AP-2 elements that bind proteins in HEK293 cells and adult kidney extracts (but not fibroblasts). The first two introns (in the untranslated region) contain transcriptional enhancer elements, demonstrated by transient transfection luciferase reporter assays.","method":"Electrophoretic mobility shift assay (EMSA), transient transfection with luciferase reporter, Northern blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional promoter/enhancer characterization using reporter assays and protein-binding assays; single lab","pmids":["12589791"],"is_preprint":false}],"current_model":"SLC7A7 encodes y+LAT1, the catalytic light subunit of the heterodimeric system y+L amino acid transporter; it requires 4F2hc (CD98) as a heavy-chain chaperone for proper trafficking from the ER/Golgi to the basolateral plasma membrane of intestinal and renal tubular epithelial cells, where—as revealed by cryo-EM structures—it uses an alternating-access mechanism with Asp243 coordinating Na+ to transport cationic amino acids (lysine, arginine, ornithine) outward in exchange for neutral amino acids inward; loss-of-function mutations cause lysinuric protein intolerance by disrupting this transport, leading to hyperammonemia, multi-organ disease, impaired IGF-1-dependent growth, defective erythropoietin-dependent erythropoiesis (cell-non-autonomously via the kidney), and macrophage-specific defects in glutamine uptake/glutaminolysis and efferocytosis; additionally, y+LAT1 restrains NFκB-mediated inflammatory signaling in macrophages and airway epithelial cells independently of its transport function, and its transcription is directly activated by CDX2 and ATF3 (the latter coupling it to mTORC1 suppression and lipogenesis control)."},"narrative":{"mechanistic_narrative":"SLC7A7 encodes y+LAT1, the catalytic light subunit of the heterodimeric system y+L amino acid transporter, which mediates cationic amino acid transport in epithelial and myeloid cells and whose loss causes lysinuric protein intolerance (LPI) [PMID:10080182, PMID:10080183]. y+LAT1 has no transport activity on its own: it must heterodimerize with the heavy chain 4F2hc (CD98), an interaction that begins in the endoplasmic reticulum and Golgi and is required to chaperone the transporter to the plasma membrane [PMID:10080182, PMID:10080183, PMID:17560897]. Cryo-EM structures of the human y+LAT1–4F2hc complex captured inward-open and outward-open states and identified Asp243 as critical for Na+ coordination and substrate selectivity, providing an alternating-access framework for cationic versus neutral amino acid handling and for the molecular impact of LPI mutations [PMID:40106545]. In epithelial cells y+LAT1 is the dominant arginine transporter and mediates basolateral arginine efflux in exchange for leucine plus sodium, explaining defective intestinal and renal handling of cationic amino acids in LPI [PMID:31705628]; paralog SLC7A6 (y+LAT2) compensates in fibroblasts but not in epithelia, partly because mutant y+LAT1 can exert a dominant-negative effect on y+LAT2 [PMID:11078698, PMID:15756301]. LPI-causing mutations either disrupt catalytic function while still reaching the membrane (e.g. L334R, G54V) or are retained intracellularly, with mutant proteins showing reduced expression and increased cytotoxicity [PMID:10655553, PMID:30832686]. Conditional and whole-body knockout mice recapitulate LPI — cationic aminoaciduria, hypoargininemia, hyperammonemia, pulmonary alveolar proteinosis, proximal tubular dysfunction, impaired skeletal development, and perinatal lethality — with citrulline rescuing the metabolic derangement [PMID:31653080, PMID:32504080], and intrauterine growth restriction linked to downregulation of hepatic IGF-1 [PMID:17376816]. Beyond transport, y+LAT1 supports macrophage biology: it is required for macrophage survival during efferocytosis [PMID:32973110] and for glutamine uptake feeding GLS1-dependent glutaminolysis and metabolic reprogramming in atherosclerosis [PMID:40983679], while defective erythropoiesis in knockout mice is cell-non-autonomous, arising from impaired renal erythropoietin production rather than loss within the erythroid or myeloid lineage [PMID:39881295]. Independently of transport, y+LAT1 restrains NFκB-driven inflammatory cytokine output in macrophages and airway epithelial cells [PMID:29616026]. SLC7A7 transcription is directly activated by the intestinal factor CDX2 [PMID:27121315] and by ATF3, the latter coupling it to suppression of mTORC1 signaling and lipogenesis [PMID:39996726].","teleology":[{"year":1999,"claim":"Establishing the gene-disease link and the obligate co-subunit requirement defined SLC7A7 as a transporter whose function depends on 4F2hc.","evidence":"Mutation identification in LPI patients plus transport reconstitution of mutant y+LAT1 with 4F2hc in Xenopus oocytes","pmids":["10080182","10080183"],"confidence":"High","gaps":["Did not resolve which cell types depend on SLC7A7 versus paralogs","No structural basis for transport or for mutation effects"]},{"year":2000,"claim":"Mutational dissection separated catalytic defects from trafficking defects, showing some LPI residues are essential for transport itself rather than membrane targeting.","evidence":"Functional and localization analysis of multiple LPI mutants in Xenopus oocytes; genomic characterization of gene structure and additional mutations","pmids":["10655553","10631139"],"confidence":"High","gaps":["Mechanism linking individual residues to catalysis not defined","Tissue specificity of the defect not yet explained"]},{"year":2000,"claim":"Discovery of paralog compensation explained why fibroblasts are spared in LPI while epithelia are not.","evidence":"Bidirectional flux and inhibitor-profiling transport assays plus mRNA analysis in LPI and control fibroblasts","pmids":["11078698"],"confidence":"Medium","gaps":["Why compensation fails in epithelia not yet mechanistically established","Single-lab functional characterization"]},{"year":2005,"claim":"A dominant-negative interaction between mutant y+LAT1 and y+LAT2 offered a mechanism for incomplete paralog rescue in LPI.","evidence":"Co-expression of E36del mutant with y+LAT2 in oocytes and mammalian cells with transport assays","pmids":["15756301"],"confidence":"Medium","gaps":["Structural basis of the proposed multiheteromeric interference unknown","Single-lab observation"]},{"year":2007,"claim":"Direct visualization of the y+LAT1–4F2hc interaction within the ER/Golgi established 4F2hc as a trafficking chaperone, not merely a surface partner.","evidence":"Acceptor-photobleaching FRET microscopy of tagged y+LAT1 and 4F2hc in HEK293 cells","pmids":["17560897"],"confidence":"High","gaps":["Did not define the assembly determinants or stoichiometry","Inference of chaperone function from interaction localization"]},{"year":2007,"claim":"A knockout mouse provided the first in vivo demonstration that Slc7a7 loss drives growth restriction via IGF-1 downregulation and reproduces human LPI metabolic features.","evidence":"Gene-trap knockout mouse with qRT-PCR, immunostaining, Western blot, and microarray profiling","pmids":["17376816"],"confidence":"High","gaps":["Neonatal lethality limited adult phenotyping","Mechanism linking transporter loss to hepatic IGF-1 not resolved"]},{"year":2013,"claim":"FRET across many LPI mutants showed heterodimer assembly is preserved, redirecting the pathogenic mechanism toward reduced expression and cytotoxicity rather than failed 4F2hc binding.","evidence":"FACS-FRET in cells co-expressing tagged y+LAT1 mutants and 4F2hc","pmids":["23940088"],"confidence":"Medium","gaps":["Cause of increased mutant-induced mortality unknown","Did not quantify residual transport for each mutant"]},{"year":2018,"claim":"Identification of an NFκB-restraining role independent of arginine levels revealed a non-transport immunomodulatory function for y+LAT1.","evidence":"siRNA knockdown with ELISA, qRT-PCR, and NFκB pathway analysis in THP-1 macrophages and A549 cells","pmids":["29616026"],"confidence":"Medium","gaps":["Molecular mechanism linking y+LAT1 to NFκB not defined","Single-lab loss-of-function"]},{"year":2019,"claim":"Quantitative transport profiling and patient-cell analysis localized the y+L defect to epithelia and myeloid cells, defining basolateral arginine efflux as the physiologically relevant activity.","evidence":"Kinetic transport assays and siRNA across MDM, Caco-2, renal and fibroblast cells; mutant localization in CHO cells and ex vivo monocytes/lymphoblasts","pmids":["31705628","30832686"],"confidence":"Medium","gaps":["Cell-type-specific expression control not fully mapped","Single-lab studies"]},{"year":2019,"claim":"An inducible knockout linked y+LAT1 deficiency to cationic amino acid depletion and hyperammonemia and demonstrated therapeutic rescue.","evidence":"Tamoxifen-inducible conditional knockout mouse with metabolic and histopathological analysis and citrulline rescue","pmids":["31653080"],"confidence":"High","gaps":["Did not dissect organ-specific contributions to hyperammonemia","Mechanism of pulmonary alveolar proteinosis not resolved"]},{"year":2020,"claim":"Genetic studies established y+LAT1 as essential for macrophage survival under high efferocytic load.","evidence":"Zebrafish genetic mutants with live imaging, lineage tracing, in vivo efferocytosis assays, and induction-kinetics measurement","pmids":["32973110"],"confidence":"High","gaps":["Metabolic substrate driving the survival requirement not identified in this model","Mammalian relevance not addressed here"]},{"year":2020,"claim":"CRISPR knockout mice consolidated the multi-organ LPI phenotype including renal tubular and skeletal defects.","evidence":"CRISPR/Cas9 knockout mouse lines with plasma/urine amino acid quantification, histopathology, and micro-CT","pmids":["32504080"],"confidence":"High","gaps":["Cell-autonomy of each organ phenotype not yet dissected","Background-dependent lethality mechanism unexplained"]},{"year":2025,"claim":"Cryo-EM structures and MD simulations delivered an atomic alternating-access mechanism, pinpointing Asp243 in Na+ coordination and rationalizing LPI mutations.","evidence":"Cryo-EM of the human y+LAT1–4F2hc complex in two conformations, molecular dynamics, and transport assays","pmids":["40106545"],"confidence":"High","gaps":["Conformational transition intermediates not captured","Structural basis of non-transport functions not addressed"]},{"year":2025,"claim":"Cell-type-specific and transplant epistasis experiments separated the transporter's metabolic roles from cell-non-autonomous phenotypes, defining glutamine-fueled glutaminolysis in macrophages and renal-EPO-dependent erythropoiesis.","evidence":"Macrophage-specific KO in atherosclerosis with glutamine flux/glutaminolysis assays; whole-body and lineage-specific KOs with bone marrow transplants for erythropoiesis","pmids":["40983679","39881295"],"confidence":"High","gaps":["Link between glutaminolysis and specific restorative macrophage programs incompletely mapped","How renal EPO production depends on the transporter not mechanistically resolved"]},{"year":2022,"claim":"Transcriptional regulators were placed upstream of SLC7A7, connecting it to mTORC1/lipogenesis control in cancer and to glucocorticoid-driven muscle metabolism.","evidence":"ATF3 gain/loss-of-function with enhancer-binding and mTORC1/lipogenesis assays in HCC; dexamethasone treatment with m6A and mTOR/protein synthesis readouts in porcine muscle cells","pmids":["39996726","35054897"],"confidence":"Medium","gaps":["Whether mTORC1 effects depend on transport activity not established","Porcine m6A finding is low-confidence and indirect"]},{"year":null,"claim":"How y+LAT1 restrains NFκB and supports macrophage survival/EPO production at a molecular level — and whether these depend on its transport activity — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No molecular intermediary linking y+LAT1 to NFκB identified","Transport-dependent versus transport-independent contributions not disentangled across functions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,13,19]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[13,20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,8,13]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[8]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,13,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12,16,20]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[15,20]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[11,18,23]}],"complexes":["y+L transporter (y+LAT1–4F2hc heterodimer)"],"partners":["SLC3A2","SLC7A6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UM01","full_name":"Y+L amino acid transporter 1","aliases":["Monocyte amino acid permease 2","MOP-2","Solute carrier family 7 member 7","y(+)L-type amino acid transporter 1","Y+LAT1","y+LAT-1"],"length_aa":511,"mass_kda":56.0,"function":"Heterodimer with SLC3A2, that functions as an antiporter which operates as an efflux route by exporting cationic amino acids from inside the cells in exchange with neutral amino acids plus sodium ions and may participate in nitric oxide synthesis via the transport of L-arginine (PubMed:10080182, PubMed:10655553, PubMed:14603368, PubMed:15756301, PubMed:15776427, PubMed:17329401, PubMed:9829974, PubMed:9878049). Also mediates arginine transport in non-polarized cells, such as monocytes, and is essential for the correct function of these cells (PubMed:15280038, PubMed:31705628). The transport mechanism is electroneutral and operates with a stoichiometry of 1:1 (By similarity). In vitro, Na(+) and Li(+), but also H(+), are cotransported with the neutral amino acids (By similarity)","subcellular_location":"Basolateral cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9UM01/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC7A7","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC7A7","total_profiled":1310},"omim":[{"mim_id":"605641","title":"SOLUTE CARRIER FAMILY 7 (CATIONIC AMINO ACID TRANSPORTER, y+ SYSTEM), MEMBER 6; SLC7A6","url":"https://www.omim.org/entry/605641"},{"mim_id":"604235","title":"SOLUTE CARRIER FAMILY 7 (CATIONIC AMINO ACID TRANSPORTER, y+ SYSTEM), MEMBER 8; 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chromosome site 14q11.","date":"1999","source":"Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/10364825","citation_count":1,"is_preprint":false},{"pmid":"21604120","id":"PMC_21604120","title":"Membrane protein digestion - comparison of LPI HexaLane with traditional techniques.","date":"2011","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/21604120","citation_count":1,"is_preprint":false},{"pmid":"41823054","id":"PMC_41823054","title":"Targeting the LPI/GPR55 Axis in MAFLD and MASH: Novel Insights, Therapeutic Strategies and Future Directions.","date":"2026","source":"Liver international : official journal of the International Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/41823054","citation_count":0,"is_preprint":false},{"pmid":"41176774","id":"PMC_41176774","title":"Single-Cell Transcriptomic Analysis Identifies a Novel OLR1+ SLC7A7+ Liver-Enriched Metastatic Subset With Immunometabolic Rewiring in Pancreatic Cancer.","date":"2025","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41176774","citation_count":0,"is_preprint":false},{"pmid":"42099775","id":"PMC_42099775","title":"SLC7A7 Downregulation in Monocytes Drives Immunosuppression and Osteosarcoma Progression.","date":"2026","source":"International journal of genomics","url":"https://pubmed.ncbi.nlm.nih.gov/42099775","citation_count":0,"is_preprint":false},{"pmid":"40596835","id":"PMC_40596835","title":"MFH-LPI: based on multi-view similarity networks fusion and hypergraph learning for long non-coding RNA-protein interactions prediction.","date":"2025","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40596835","citation_count":0,"is_preprint":false},{"pmid":"41821046","id":"PMC_41821046","title":"Monogenic lupus with SLC7A7 mutations: a retrospective study from a Chinese center.","date":"2026","source":"Orphanet journal of rare 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cancer","date":"2025-04-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.03.25325183","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46402,"output_tokens":6374,"usd":0.117408,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15218,"output_tokens":4869,"usd":0.098907,"stage2_stop_reason":"end_turn"},"total_usd":0.216315,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"SLC7A7 (encoding y+LAT-1) was identified as the gene mutated in lysinuric protein intolerance (LPI); a missense mutation in y+LAT-1 abolishes dibasic amino acid (cationic amino acid) transport activity when co-expressed with the heavy chain of 4F2hc (CD98) in Xenopus laevis oocytes, establishing that y+LAT-1 requires 4F2hc as a co-subunit for transport function.\",\n      \"method\": \"Mutation identification in patients + functional expression assay in Xenopus oocytes + transport activity measurement\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct transport reconstitution in oocytes with mutagenesis, replicated across two independent papers in the same issue\",\n      \"pmids\": [\"10080182\", \"10080183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Five LPI-causing mutations (L334R, G54V, 1291delCTTT, 1548delC, and LPIFin) were functionally characterized: all abolished y+L amino acid transport when co-expressed with 4F2hc in Xenopus oocytes. Frameshift mutants (1291delCTTT, 1548delC, LPIFin) were retained intracellularly, while missense mutants L334R and G54V reached the plasma membrane, demonstrating that residues L334 and G54 are critical for transport catalytic function rather than membrane targeting.\",\n      \"method\": \"Expression in Xenopus oocytes, transport activity assays, immunostaining/subcellular localization\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in oocytes with multiple mutants, mutagenesis coupled to localization, orthogonal methods in one study\",\n      \"pmids\": [\"10655553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SLC7A7 (y+LAT-1) gene comprises 10 exons; novel LPI mutations include missense M1L (start codon change), missense S386R, nonsense W242X, splice mutations IVS3+1G>A and IVS6+1G>T, insertion 786insT, and deletions 455delCTCT and 1425delTTCT, all causing loss of functional cationic amino acid transport.\",\n      \"method\": \"Genomic sequencing, mutational analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mutational characterization of gene structure with multiple mutations identified; no functional reconstitution per abstract\",\n      \"pmids\": [\"10631139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"In LPI fibroblasts, arginine transport through system y+L is normal (not defective), attributable to SLC7A6 (y+LAT2) activity rather than SLC7A7 (y+LAT1), demonstrating cell-type-specific compensation between paralogs. Both SLC7A7 and SLC7A6 are expressed in fibroblasts, and the LPI transport defect is limited to epithelial cells where SLC7A7 predominates.\",\n      \"method\": \"Amino acid transport characterization (bidirectional flux assays, inhibitor profiling with NEM, membrane potential, Na+ dependence) in patient-derived and control fibroblasts; mRNA expression analysis\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transport characterization in primary patient cells with multiple pharmacological inhibitors; single lab\",\n      \"pmids\": [\"11078698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The LPI-causing y+LAT-1 mutant E36del displays a partial dominant-negative effect on y+LAT-2 activity when co-expressed in Xenopus oocytes and mammalian cells, suggesting a multiheteromeric structure for both [4F2hc/y+LAT-1] and [4F2hc/y+LAT-2] complexes and interference between y+LAT-1 and y+LAT-2 proteins that can explain why upregulation of SLC7A6 does not fully compensate for SLC7A7 loss in LPI.\",\n      \"method\": \"Expression in Xenopus laevis oocytes and mammalian cells, transport activity assays, dominant-negative functional analysis\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct transport reconstitution with mutants in oocytes and mammalian cells; single lab, partial mechanistic follow-up\",\n      \"pmids\": [\"15756301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Functional analysis of eight SLC7A7 mutations by expression in Xenopus oocytes or patient renal tubular cells revealed loss of y+L transport activity. The R333M mutation disrupts a functional splicing motif (last nucleotide of exon 7), generating misspliced transcripts in addition to protein dysfunction.\",\n      \"method\": \"Expression in Xenopus oocytes, transport activity assay, analysis of patient renal tubular cells, splicing analysis\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — transport reconstitution in oocytes and patient cells; single lab\",\n      \"pmids\": [\"15776427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"y+LAT-1 (SLC7A7) is the transporter responsible for uptake of the iNOS inhibitor GW274150 in murine macrophage J774 cells, operating via system y+L (Na+-independent, trans-stimulated, inhibited by cationic amino acids and neutral amino acids in a Na+-dependent manner). Northern blot confirmed expression of y+LAT-1 but not y+LAT-2 transcripts in these cells.\",\n      \"method\": \"Saturable transport assay with pharmacological profiling (inhibitors, ion substitution, trans-stimulation), Northern blot\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — detailed kinetic and pharmacological transport characterization; single lab, two orthogonal methods\",\n      \"pmids\": [\"16699825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Two alternative promoters regulate SLC7A7 expression: a novel TATA-box-containing downstream promoter upstream of exon 2 is active in tissues with strong cationic amino acid transport defects in LPI patients, revealing tissue-specific transcriptional regulation of the gene.\",\n      \"method\": \"Promoter identification and analysis, tissue-specific expression studies\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct identification of alternative promoter with functional evidence; single lab, single study\",\n      \"pmids\": [\"17196863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"y+LAT-1 and 4F2hc form a heterodimer that assembles prior to reaching the plasma membrane; FRET (acceptor photobleaching) microscopy in HEK293 cells showed the interaction occurring in the endoplasmic reticulum and Golgi complex as well as at the plasma membrane, providing direct evidence that 4F2hc acts as a chaperone to assist trafficking of y+LAT-1 to the plasma membrane.\",\n      \"method\": \"Acceptor photobleaching FRET microscopy in HEK293 cells expressing fluorescently-tagged y+LAT-1 (ECFP) and 4F2hc (EYFP)\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct FRET measurement in intact cells demonstrating protein-protein interaction at specific subcellular compartments with functional chaperone inference; single lab with rigorous optical method\",\n      \"pmids\": [\"17560897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Slc7a7 knockout mice (gene-trap retroviral insertion) exhibit intrauterine growth restriction (IUGR) and neonatal lethality. IUGR is mechanistically linked to marked downregulation of insulin-like growth factor 1 (IGF-1) in fetal liver, demonstrated by quantitative real-time RT-PCR, immunostaining, and Western blot. Adult surviving Slc7a7-/- mice show metabolic derangement consistent with human LPI after protein ingestion.\",\n      \"method\": \"Mouse knockout (retroviral gene-trap), quantitative RT-PCR, immunostaining, Western blot, DNA microarray gene expression profiling\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mouse model with defined molecular phenotype (IGF-1 downregulation), three orthogonal quantification methods; published in peer-reviewed journal\",\n      \"pmids\": [\"17376816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FACS-FRET analysis confirmed that heteromerization of y+LAT1 with 4F2hc is not disrupted by any tested LPI mutations (including missense and frameshift mutants), but LPI mutant y+LAT1 proteins are expressed at significantly lower levels and cause markedly increased cellular mortality compared to wild-type y+LAT1.\",\n      \"method\": \"FACS-FRET (flow cytometry-based FRET) in cells expressing CFP-tagged y+LAT1 and YFP-tagged 4F2hc\",\n      \"journal\": \"General physiology and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET-based protein interaction assay with multiple LPI mutants; single lab\",\n      \"pmids\": [\"23940088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CDX2, an intestine-specific transcription factor, directly binds the SLC7A7 promoter (demonstrated by luciferase reporter and chromatin immunoprecipitation assays) and activates SLC7A7 transcription, establishing SLC7A7 as a direct CDX2 target gene in intestinal epithelial cells.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), overexpression in IPEC-1 cells\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (reporter assay and ChIP) in a single study; single lab\",\n      \"pmids\": [\"27121315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Silencing of SLC7A7/y+LAT1 in human THP-1 macrophages and A549 airway epithelial cells via siRNA induces expression and release of IL-1β and TNFα independent of intracellular arginine levels, via activation of the NFκB signaling pathway at the transcriptional level. Furthermore, SLC7A7 silencing potentiates IL-1β-stimulated CCL5/RANTES expression without affecting CXCL8/IL-8, revealing a non-transport immunomodulatory function of y+LAT1.\",\n      \"method\": \"siRNA knockdown, ELISA, qRT-PCR, NFκB pathway analysis in THP-1 macrophages and A549 cells\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular pathway (NFκB) using multiple cell types and multiple readouts; single lab\",\n      \"pmids\": [\"29616026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"y+LAT1 (SLC7A7) is the dominant arginine transporter in monocyte-derived macrophages and intestinal Caco-2 cells, while y+LAT2 (SLC7A6) dominates in fibroblasts. At the basolateral side of Caco-2 cells, system y+L mediates arginine efflux in exchange with leucine plus sodium, explaining defective intestinal absorption/reabsorption of arginine in LPI.\",\n      \"method\": \"Kinetic transport assays, mRNA expression analysis across multiple human cell types (MDM, Caco-2, HRPTEpC, fibroblasts), siRNA knockdown\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative transport kinetics across multiple cell types with molecular identification; single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"31705628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Three LPI-causing y+LAT1 mutations reproduced as eGFP-tagged proteins in CHO cells result in defective arginine transport and retention of the mutant proteins in the cytosol (confirmed by confocal microscopy), with heterogeneous subcellular distribution patterns among mutants. System y+L activity is impaired in monocytes from LPI patients but not in lymphoblasts carrying the same mutations, attributed to differential SLC7A7 mRNA expression between cell types.\",\n      \"method\": \"eGFP-tagged mutant expression in CHO cells, confocal microscopy, transport assays in transfected CHO cells and ex vivo patient monocytes/lymphoblasts\",\n      \"journal\": \"Orphanet journal of rare diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transport assay plus direct localization microscopy in two model systems; single lab\",\n      \"pmids\": [\"30832686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A tamoxifen-inducible Slc7a7 knockout mouse recapitulates human LPI phenotype including malabsorption and impaired reabsorption of cationic amino acids, hypoargininemia, hyperammonemia, pulmonary alveolar proteinosis, and neurological impairment. Citrulline treatment improves metabolic derangement and survival, confirming the mechanistic link between y+LAT1 deficiency, cationic amino acid depletion, and hyperammonemia.\",\n      \"method\": \"Tamoxifen-inducible conditional knockout mouse, metabolic analysis (plasma/urine amino acids), histopathology, citrulline rescue experiment\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible KO mouse with defined metabolic phenotype, multiple organ systems analyzed, pharmacological rescue; peer-reviewed\",\n      \"pmids\": [\"31653080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In zebrafish, Slc7a7 is the main cationic amino acid transporter expressed in macrophages; its expression is induced within 1–2 hours upon efferocytosis (phagocytosis of apoptotic cells). Slc7a7-deficient macrophages that engage in sustained efferocytic work die, demonstrating that Slc7a7 is required for macrophage survival during intense phagocytic activity, likely to cope with catabolism of dead cell material.\",\n      \"method\": \"Zebrafish genetic mutant screen, live imaging, macrophage lineage tracing, in vivo efferocytosis assay, gene expression analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function in zebrafish with defined cellular phenotype (macrophage death upon efferocytosis), induction kinetics measured, orthogonal in vivo and molecular methods\",\n      \"pmids\": [\"32973110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Global Slc7a7 knockout mice (CRISPR/Cas9, exons 3–4 deletion) on mixed background display reduced plasma and increased urinary cationic amino acids, proximal tubular dysfunction (loss of brush border, lipid vacuolation in renal cortex), delayed skeletal development with decreased mineralization, and perinatal lethality on inbred backgrounds, recapitulating human LPI.\",\n      \"method\": \"CRISPR/Cas9 knockout mouse generation, amino acid quantification in plasma/urine, histopathology, micro-computed tomography\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent CRISPR KO mouse lines with defined molecular and organ phenotypes; peer-reviewed\",\n      \"pmids\": [\"32504080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATF3 transcriptionally activates SLC7A7 by binding to its enhancer region, and through this axis suppresses mTORC1 signaling to inhibit lipogenesis in hepatocellular carcinoma (HCC). Functional assays in ATF3-overexpressing and knockdown HCC cell lines confirmed that SLC7A7 acts downstream of ATF3 to restrain mTORC1 activity.\",\n      \"method\": \"Transcriptomic analysis, ATF3 overexpression/knockdown in HCC cell lines, chromatin/enhancer binding assay, mTORC1 activity assay, lipogenesis assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function experiments with defined signaling pathway placement; single lab\",\n      \"pmids\": [\"39996726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of the human y+LAT1–4F2hc complex were determined in two conformations: apo inward-open and substrate-bound outward-open states. Structural analysis identified Asp243 in y+LAT1 as critical for sodium ion coordination and substrate selectivity. Molecular dynamics simulations revealed different transport mechanisms for cationic versus neutral amino acids, and the structural framework explained the molecular basis of LPI-causing mutations.\",\n      \"method\": \"Cryo-EM structure determination (two conformations), molecular dynamics simulation, functional transport assay in mammalian cells\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures at two conformational states with functional transport validation and MD simulations; single study with multiple orthogonal methods\",\n      \"pmids\": [\"40106545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Macrophage-specific deletion of Slc7a7 in atherosclerotic mice accelerates disease with more complex necrotic core composition. Slc7a7-silenced macrophages have reduced glutamine influx and reduced GLS1-dependent glutaminolysis, impairing downstream signaling for restorative macrophage functions. This establishes SLC7A7-dependent glutamine uptake as upstream of glutaminolysis and macrophage metabolic reprogramming in atherosclerosis.\",\n      \"method\": \"Macrophage-specific conditional Slc7a7 knockout in atherosclerosis mouse model, in vitro Slc7a7 silencing, glutamine flux measurement, glutaminolysis assay, histopathology\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO in disease model with defined metabolic mechanism (glutamine influx/glutaminolysis), in vitro and in vivo validation, peer-reviewed\",\n      \"pmids\": [\"40983679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Defective erythropoiesis in Slc7a7 whole-body knockout mice is not caused by intrinsic loss of Slc7a7 in erythroblasts or myeloid cells (erythroblast- and myeloid-specific KOs do not recapitulate the phenotype; bone marrow transplants do not rescue), but is linked to impaired erythropoietin production in the kidney and subsequent iron overload.\",\n      \"method\": \"Whole-body and cell-type-specific conditional Slc7a7 knockouts (erythroblast- and myeloid-specific), bone marrow transplantation experiments, erythropoiesis analysis, erythropoietin measurement\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional KO models plus bone marrow transplant epistasis experiments definitively localizing the cell-non-autonomous defect; peer-reviewed\",\n      \"pmids\": [\"39881295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Glucocorticoid (dexamethasone) reduces SLC7A7 expression in porcine skeletal muscle cells via changes in m6A mRNA modification, and reduced SLC7A7 expression in turn reduces mTOR signaling pathway activity and protein synthesis.\",\n      \"method\": \"Dexamethasone treatment of porcine skeletal muscle cells, m6A modification analysis, mTOR pathway readouts, protein synthesis assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect pathway placement via m6A and mTOR readouts in porcine cells with limited mechanistic detail in abstract\",\n      \"pmids\": [\"35054897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The SLC7A7 promoter region (upstream of exon 1) lacks classical TATA-box and Inr elements but contains E-box and AP-2 elements that bind proteins in HEK293 cells and adult kidney extracts (but not fibroblasts). The first two introns (in the untranslated region) contain transcriptional enhancer elements, demonstrated by transient transfection luciferase reporter assays.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), transient transfection with luciferase reporter, Northern blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional promoter/enhancer characterization using reporter assays and protein-binding assays; single lab\",\n      \"pmids\": [\"12589791\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC7A7 encodes y+LAT1, the catalytic light subunit of the heterodimeric system y+L amino acid transporter; it requires 4F2hc (CD98) as a heavy-chain chaperone for proper trafficking from the ER/Golgi to the basolateral plasma membrane of intestinal and renal tubular epithelial cells, where—as revealed by cryo-EM structures—it uses an alternating-access mechanism with Asp243 coordinating Na+ to transport cationic amino acids (lysine, arginine, ornithine) outward in exchange for neutral amino acids inward; loss-of-function mutations cause lysinuric protein intolerance by disrupting this transport, leading to hyperammonemia, multi-organ disease, impaired IGF-1-dependent growth, defective erythropoietin-dependent erythropoiesis (cell-non-autonomously via the kidney), and macrophage-specific defects in glutamine uptake/glutaminolysis and efferocytosis; additionally, y+LAT1 restrains NFκB-mediated inflammatory signaling in macrophages and airway epithelial cells independently of its transport function, and its transcription is directly activated by CDX2 and ATF3 (the latter coupling it to mTORC1 suppression and lipogenesis control).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC7A7 encodes y+LAT1, the catalytic light subunit of the heterodimeric system y+L amino acid transporter, which mediates cationic amino acid transport in epithelial and myeloid cells and whose loss causes lysinuric protein intolerance (LPI) [#0]. y+LAT1 has no transport activity on its own: it must heterodimerize with the heavy chain 4F2hc (CD98), an interaction that begins in the endoplasmic reticulum and Golgi and is required to chaperone the transporter to the plasma membrane [#0, #8]. Cryo-EM structures of the human y+LAT1\\u20134F2hc complex captured inward-open and outward-open states and identified Asp243 as critical for Na+ coordination and substrate selectivity, providing an alternating-access framework for cationic versus neutral amino acid handling and for the molecular impact of LPI mutations [#19]. In epithelial cells y+LAT1 is the dominant arginine transporter and mediates basolateral arginine efflux in exchange for leucine plus sodium, explaining defective intestinal and renal handling of cationic amino acids in LPI [#13]; paralog SLC7A6 (y+LAT2) compensates in fibroblasts but not in epithelia, partly because mutant y+LAT1 can exert a dominant-negative effect on y+LAT2 [#3, #4]. LPI-causing mutations either disrupt catalytic function while still reaching the membrane (e.g. L334R, G54V) or are retained intracellularly, with mutant proteins showing reduced expression and increased cytotoxicity [#1, #14]. Conditional and whole-body knockout mice recapitulate LPI \\u2014 cationic aminoaciduria, hypoargininemia, hyperammonemia, pulmonary alveolar proteinosis, proximal tubular dysfunction, impaired skeletal development, and perinatal lethality \\u2014 with citrulline rescuing the metabolic derangement [#15, #17], and intrauterine growth restriction linked to downregulation of hepatic IGF-1 [#9]. Beyond transport, y+LAT1 supports macrophage biology: it is required for macrophage survival during efferocytosis [#16] and for glutamine uptake feeding GLS1-dependent glutaminolysis and metabolic reprogramming in atherosclerosis [#20], while defective erythropoiesis in knockout mice is cell-non-autonomous, arising from impaired renal erythropoietin production rather than loss within the erythroid or myeloid lineage [#21]. Independently of transport, y+LAT1 restrains NF\\u03baB-driven inflammatory cytokine output in macrophages and airway epithelial cells [#12]. SLC7A7 transcription is directly activated by the intestinal factor CDX2 [#11] and by ATF3, the latter coupling it to suppression of mTORC1 signaling and lipogenesis [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing the gene-disease link and the obligate co-subunit requirement defined SLC7A7 as a transporter whose function depends on 4F2hc.\",\n      \"evidence\": \"Mutation identification in LPI patients plus transport reconstitution of mutant y+LAT1 with 4F2hc in Xenopus oocytes\",\n      \"pmids\": [\"10080182\", \"10080183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which cell types depend on SLC7A7 versus paralogs\", \"No structural basis for transport or for mutation effects\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mutational dissection separated catalytic defects from trafficking defects, showing some LPI residues are essential for transport itself rather than membrane targeting.\",\n      \"evidence\": \"Functional and localization analysis of multiple LPI mutants in Xenopus oocytes; genomic characterization of gene structure and additional mutations\",\n      \"pmids\": [\"10655553\", \"10631139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking individual residues to catalysis not defined\", \"Tissue specificity of the defect not yet explained\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Discovery of paralog compensation explained why fibroblasts are spared in LPI while epithelia are not.\",\n      \"evidence\": \"Bidirectional flux and inhibitor-profiling transport assays plus mRNA analysis in LPI and control fibroblasts\",\n      \"pmids\": [\"11078698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why compensation fails in epithelia not yet mechanistically established\", \"Single-lab functional characterization\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"A dominant-negative interaction between mutant y+LAT1 and y+LAT2 offered a mechanism for incomplete paralog rescue in LPI.\",\n      \"evidence\": \"Co-expression of E36del mutant with y+LAT2 in oocytes and mammalian cells with transport assays\",\n      \"pmids\": [\"15756301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the proposed multiheteromeric interference unknown\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Direct visualization of the y+LAT1\\u20134F2hc interaction within the ER/Golgi established 4F2hc as a trafficking chaperone, not merely a surface partner.\",\n      \"evidence\": \"Acceptor-photobleaching FRET microscopy of tagged y+LAT1 and 4F2hc in HEK293 cells\",\n      \"pmids\": [\"17560897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the assembly determinants or stoichiometry\", \"Inference of chaperone function from interaction localization\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A knockout mouse provided the first in vivo demonstration that Slc7a7 loss drives growth restriction via IGF-1 downregulation and reproduces human LPI metabolic features.\",\n      \"evidence\": \"Gene-trap knockout mouse with qRT-PCR, immunostaining, Western blot, and microarray profiling\",\n      \"pmids\": [\"17376816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neonatal lethality limited adult phenotyping\", \"Mechanism linking transporter loss to hepatic IGF-1 not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"FRET across many LPI mutants showed heterodimer assembly is preserved, redirecting the pathogenic mechanism toward reduced expression and cytotoxicity rather than failed 4F2hc binding.\",\n      \"evidence\": \"FACS-FRET in cells co-expressing tagged y+LAT1 mutants and 4F2hc\",\n      \"pmids\": [\"23940088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cause of increased mutant-induced mortality unknown\", \"Did not quantify residual transport for each mutant\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of an NF\\u03baB-restraining role independent of arginine levels revealed a non-transport immunomodulatory function for y+LAT1.\",\n      \"evidence\": \"siRNA knockdown with ELISA, qRT-PCR, and NF\\u03baB pathway analysis in THP-1 macrophages and A549 cells\",\n      \"pmids\": [\"29616026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking y+LAT1 to NF\\u03baB not defined\", \"Single-lab loss-of-function\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Quantitative transport profiling and patient-cell analysis localized the y+L defect to epithelia and myeloid cells, defining basolateral arginine efflux as the physiologically relevant activity.\",\n      \"evidence\": \"Kinetic transport assays and siRNA across MDM, Caco-2, renal and fibroblast cells; mutant localization in CHO cells and ex vivo monocytes/lymphoblasts\",\n      \"pmids\": [\"31705628\", \"30832686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type-specific expression control not fully mapped\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"An inducible knockout linked y+LAT1 deficiency to cationic amino acid depletion and hyperammonemia and demonstrated therapeutic rescue.\",\n      \"evidence\": \"Tamoxifen-inducible conditional knockout mouse with metabolic and histopathological analysis and citrulline rescue\",\n      \"pmids\": [\"31653080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not dissect organ-specific contributions to hyperammonemia\", \"Mechanism of pulmonary alveolar proteinosis not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic studies established y+LAT1 as essential for macrophage survival under high efferocytic load.\",\n      \"evidence\": \"Zebrafish genetic mutants with live imaging, lineage tracing, in vivo efferocytosis assays, and induction-kinetics measurement\",\n      \"pmids\": [\"32973110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Metabolic substrate driving the survival requirement not identified in this model\", \"Mammalian relevance not addressed here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"CRISPR knockout mice consolidated the multi-organ LPI phenotype including renal tubular and skeletal defects.\",\n      \"evidence\": \"CRISPR/Cas9 knockout mouse lines with plasma/urine amino acid quantification, histopathology, and micro-CT\",\n      \"pmids\": [\"32504080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-autonomy of each organ phenotype not yet dissected\", \"Background-dependent lethality mechanism unexplained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-EM structures and MD simulations delivered an atomic alternating-access mechanism, pinpointing Asp243 in Na+ coordination and rationalizing LPI mutations.\",\n      \"evidence\": \"Cryo-EM of the human y+LAT1\\u20134F2hc complex in two conformations, molecular dynamics, and transport assays\",\n      \"pmids\": [\"40106545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational transition intermediates not captured\", \"Structural basis of non-transport functions not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cell-type-specific and transplant epistasis experiments separated the transporter's metabolic roles from cell-non-autonomous phenotypes, defining glutamine-fueled glutaminolysis in macrophages and renal-EPO-dependent erythropoiesis.\",\n      \"evidence\": \"Macrophage-specific KO in atherosclerosis with glutamine flux/glutaminolysis assays; whole-body and lineage-specific KOs with bone marrow transplants for erythropoiesis\",\n      \"pmids\": [\"40983679\", \"39881295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between glutaminolysis and specific restorative macrophage programs incompletely mapped\", \"How renal EPO production depends on the transporter not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Transcriptional regulators were placed upstream of SLC7A7, connecting it to mTORC1/lipogenesis control in cancer and to glucocorticoid-driven muscle metabolism.\",\n      \"evidence\": \"ATF3 gain/loss-of-function with enhancer-binding and mTORC1/lipogenesis assays in HCC; dexamethasone treatment with m6A and mTOR/protein synthesis readouts in porcine muscle cells\",\n      \"pmids\": [\"39996726\", \"35054897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mTORC1 effects depend on transport activity not established\", \"Porcine m6A finding is low-confidence and indirect\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How y+LAT1 restrains NF\\u03baB and supports macrophage survival/EPO production at a molecular level \\u2014 and whether these depend on its transport activity \\u2014 remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular intermediary linking y+LAT1 to NF\\u03baB identified\", \"Transport-dependent versus transport-independent contributions not disentangled across functions\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 13, 19]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [13, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 8, 13]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 13, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 16, 20]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [15, 20]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [11, 18, 23]}\n    ],\n    \"complexes\": [\"y+L transporter (y+LAT1\\u20134F2hc heterodimer)\"],\n    \"partners\": [\"SLC3A2\", \"SLC7A6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}